The immune response against Mycobacterium tuberculosis results in control, but not elimination, of infection. T cells are a crucial component of this response. This proposal extends our current work on examining the CD8 T cell subset and the effect of these cells in tuberculosis. It is clear that the naturally induced immune response is insufficient to resolve a M. tuberculosis infection. Understanding how the CD8 T cell response develops and is modulated over the course of infection may provide clues to augmenting this response to provide better control of infection. In this proposal, we will focus on following CD8 T cell responses to specific antigens, focusing on the function of the CD8 T cells at various times post-infection. Specifically, cytokine production and cytotoxic ability will be tested during acute, chronic, memory and reactivation states. Our hypothesis is that the CD8 T cell response and function wane during a chronic infection, and boosting this response would result in improved control of the infection. In addition, preliminary data indicates a role for CD4 T cells in maintaining CD8 CTL function, and the mechanisms responsible for this will be investigated. Our long term goal is to have a clear picture of the CD8 T cell response in tuberculosis, including antigen specificity, function, evolution, and maintenance. This information will impact directly on vaccine development, since it appears that stimulation of both CD4 and CD8 T cells will be necessary to provide adequate protection against tuberculosis. To this end, our specific aims are: Aim 1. To examine evolution in the antigen specific CD8 T cell responses during M. tuberculosis infection. Aim 2: To investigate the function of CD8 T cells in M. tuberculosis infection. Aim 3: To assess the development, maintenance and function of memory and recall CD8 T cell responses in tuberculosis. Aim 4: To determine the effects of CD4 T cells on CD8 T cell maintenance and function in tuberculosis. Animal models will be used in these studies, and we have adapted a variety of functional assays for CD8 T cells for use with lung cells. These complementary aims will provide a definitive picture of the CD8 T cell response in tuberculosis, and contribute to a greater understanding of the challenges facing vaccine development and design against this disease.